The immune system has evolved specifically to detect and eliminate foreign or new material from a host. This material may be of viral, bacterial, or parasitic origin and may reside outside or within the cells of the host, or be of neoplastic origin. It may also be from other sources and not pathogenic or not intrinsically damaging to all subjects.
The mucosal immune system (MIS) consists of lymphoid tissues within and directly beneath the epithelial lining of the respiratory, genitourinary and gastrointestinal tract as well as beneath the ductal system of the salivary, lacrimal and mammary glands. The primary product of the MIS is IgA.
Vaccination is the best known and most successful application of an immunological principle to human health. Naturally, to be introduced and approved, a vaccine must be effective and the efficacy of all vaccines is reviewed from time to time. Many factors affect the efficacy of a vaccine. For example, a vaccine is usually administered by the subcutaneous or intramuscular route. Recently the sublingual route has been used for administration of therapeutic allergy vaccines. An effective vaccine must induce the appropriate immunity in terms of quantitative and qualitative effects and be stable on storage. With non-living vaccines in particular, it is often necessary to boost their immunogenicity with an adjuvant. This can also apply to some live, e.g. attenuated vaccines. An adjuvant is a substance that enhances the immune response to an antigen.
During work in the 1920s on the production of animal antiserum for human therapy, it was discovered that certain substances, notably aluminium salts added to antigens or emulsions incorporating antigen, greatly enhance antibody production, i.e. they act as adjuvants. Aluminium hydroxide is still widely used with, e.g. diphtheria and tetanus toxoid and insoluble tyrosine is used with some allergy vaccines. Other more soluble adjuvants also have desirable effects such as inducing a heightened immune response or driving the response towards for example a TH1 type response.
3 De-O-acylated monophosphoryl lipid A is known from GB-A-2220211 (Ribi). Chemically it can be a mixture of 3 de-O-acylated monophosphoryl lipid A with 4, 5 or 6 acylated chains and is now manufactured by Corixa Corporation. A preferred form of 3 de-O-acylated monophosphoryl lipid A (also referred to herein as MPL® adjuvant) is disclosed in International Patent Application No. WO92/16556.
International Patent Publication No. WO98/44947 described a formulation for use in desensitisation therapy of allergy sufferers which comprised an optionally modified allergen, tyrosine and 3 de-O-acylated monophosphoryl lipid A.
Considerable efforts have been made to produce better adjuvants, particularly for T-cell-mediated responses, but it should be stressed that few of these more recent adjuvants are yet accepted for routine human use. MPL® adjuvant, however, has been licensed for use with a Melanoma vaccine and allergy vaccines containing MPL® adjuvant are available as ‘Specials’ in Germany, Italy and Spain.
WO00/50078 to Chiron describes a composition which includes bioadhesives in combination with adjuvants and antigens for mucosal delivery. However, it only demonstrates the production of an IgG immune response with the composition. Further, the bioadhesive is an agent which physically or chemically binds to mucus. It is believed that there may be safety concerns associated with such bioadhesion of some antigen-containing compositions. Sublingual delivery is not taught; the test composition being administered intranasally.
Clearly there is still a need for a composition that generates a mucosal and systemic inrune response to protect against bacteria, viruses and other parasitic organisms, and that may be used as an allergy vaccine. Ideally such a composition should be administerable via a route which is associated with good patient compliance, such as the sublingual route. It has also been found that sublingual delivery may give rapid absorption and good bioavailability of the substance being delivered. Sublingual delivery may also be advantageous over intermittent injections in maintaining adequate blood concentrations of the substance being delivered. Preferably the composition should make use of conveniently available adjuvants.